The herpesviruses, herpes simplex virus (HSV) and human cytomegalovirus (CMV), are two important human pathogens for which there is a critical need to develop safe, effective antiviral agents. HSV is amenable to a variety of molecular and genetic tools that can be brought to bear on a problem. Concepts developed in the HSV system frequently are then applicable to CMV. The long term objective of the proposed research is to identify, characterize, and exploit drug targets of HSV and CMV. The existence of these targets is, or will be, inferred from mutants that exhibit altered sensitivity to previously existing drugs. The information derived from molecular characterization of these targets will be used to tailor new, more effective anti- herpesvirus drugs. This approach combines advantages of a random screening approach, which automatically selects targets for those kinds of small molecules that make useful drugs, and targeted approaches, in which molecular knowledge is used for drug design. Three classes of drugs will be developed. The first class will be synthetic peptides derived from the HSV DNA polymerase that disrupt the interaction of the HSV DNA polymerase and the major HSV DNA binding protein. The second class will be nucleoside analogs that are activated by a CMV function, newly identified by a drug resistant mutant, that contributes to the specific activation of ganciclovir (DHPG). The third class will be defined by the molecular characterization of drug targets identified by isolation and analysis of mutants of HSV and CMV that are resistant to drugs that act selectively against these viruses by unknown mechanisms.